Highly Stereoselective [3+2] Cycloadditions of Nitrile Oxides to Methyl 4-O-Acryloyl-6-deoxy-2,3-O-(t-butyldimethylsilyl)-α-d-glucopyranoside

Abstract

The [3+2] cycloadditions of benzonitrile oxide or pivalo­nitrile oxide to methyl 4-O-acryloyl-6-deoxy-2,3-di-O-(t-butyl­dimethylsilyl)-α-d-glucopyranoside provided the respective adducts, each as virtually a single diastereomer. By reductive remova­l of the carbohydrate template from each adduct, the respectiv­e (R)-enriched Δ²-isoxazoline derivative was obtained.

Key words

asymmetric synthesis - [3+2] cycloadditions - nitrile oxide­s - d-glucose - chiral auxiliary

References and Notes

• 1a Cintas P. Tetrahedron  1991,  47:  6079 
• 1b Seyden-Penne J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis   Wiley; New York: 1995. 
• 1c Kunz H. Angew. Chem., Int. Ed. Engl.  1993,  32:  336 
• 1d Rück K. Kunz H. Chiral Auxiliaries in Cycloadditions   Wiley; New York: 1995. 
• 1e Hultin PG. Earle MA. Sudharshan M. Tetrahedron  1997,  53:  14823 
• 2a Totani K. Nagatsuka T. Takao K. Ohba S. Tadano K. Org. Lett.  1999,  1:  1447 
• 2b Munakata R. Totani K. Takao K. Tadano K. Synlett  2000,  979 
• 2c Nagatuska T. Yamaguchi S. Totani K. Takao K. Tadano K. Synlett  2001,  481 
• 2d Totani K. Nagatsuka T. Yamaguchi S. Takao K. Ohba S. Tadano K. J. Org. Chem.  2001,  66:  5965 
• 2e Nagatsuka T. Yamaguchi S. Totani K. Takao K. Tadano K. J. Carbohydr. Chem.  2001,  20:  519 
• 2f Totani K. Asano S. Takao K. Tadano K. Synlett  2001,  1772 
• 3a For a recent review on [3+2] cycloadditions, see: Gothelf KV. Jorgensen KA. Chem. Rev.  1998,  98:  863 
• 3b For a recent paper on the sugar-based stereoselective [3+2] cycloadditions of nitrile oxide, see: Desroses M. Chéry F. Tatibouët A. De Lucchi O. Rollin P. Tetrahedron: Asymmetry  2002,  13:  2535 
• 4a Hassner A. Rai KML. Synthesis  1989,  57 
• 4b Rai KML. Hassner A. Indian J. Chem., Sect. B  1997,  36:  242 
• 14 Curran DP. Kim BH. Piyasena HP. Loncharich RJ. Houk KN. J. Org. Chem.  1987,  52:  2137 
• 15 The new template 9 was prepared from known compound 11 as shown below (Scheme 4). Compound 11 was prepared from tri-O-acetyl-d-glucal according to the reported procedure: Giuliano RM. Jordan AD. Gauthier AD. Hoogsteen K. J. Org. Chem.  1993,  58:  4979 

5

All new compounds gave spectroscopic data (¹H, ¹³C NMR, IR, and HRMS) in agreement with the structures depicted. Yields refer to purified sample by chromatography on silica gel.

6

The [3+2] Cycloaddition of 2 using Benzonitrile Oxide in CH₂Cl₂; Preparation of Methyl 6-deoxy-4-O-[(5R)-3-phenyl-Δ²-isoxazoline-5-carbonyl]-2,3-di-O-t-butyldimethylsilyl-α-d-glucopyranoside (3 R). To a cooled (0 °C) stirred solution of 2 (211 mg, 0.459 mmol) in CH₂Cl₂ (4 mL) was added benzonitrile oxide (274 mg, 2.28 mmol). The mixture was stirred at r.t. for 4 h, then diluted with EtOAc (20 mL), and washed with sat. aq NH₄Cl (10 mL
× 3). The organic layer was dried over anhyd Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc-hexane = 1:40) to give 262 mg (96%) of 3 R as colorless oil. Compound 3 R: TLC, R_f 0.47 (EtOAc-hexane = 1:6); IR(neat): 3100-2800, 1750, 1600 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ: 0.10, 0.11, 0.12 (total 12 H, 3s), 0.85, 0.93 (each 9 H, each s), 1.10 (3 H, d, J = 6.6 Hz), 3.37 (3 H, s), 3.52 (1 H, dd, J = 11.2, 16.8 Hz), 3.67 (1 H, dd, J = 3.7, 9.2 Hz), 3.80 (1 H, dd, J = 6.3, 16.8 Hz), 3.83 (1 H, m), 4.01 (1 H, t, J = 9.2 Hz), 4.62 (1 H, d, J = 3.7 Hz), 4.74 (1 H, dd, J = 9.2, 9.9 Hz), 5.14 (1 H, dd, J = 6.3, 11.2 Hz), 7.40-7.70 (5 H, m); ¹³C NMR (75 MHz, CDCl₃) δ: -4.49, -4.39, -3.39, -3.06, 17.32, 17.88, 18.41, 25.87 × 3, 26.12 × 3, 38.00, 54.92, 65.16, 71.62, 74.45, 78.12, 78.58, 100.06, 126.94 × 2, 128.77 × 2, 130.53 × 2, 156.37, 169.40; HRMS: m/z calcd for C₂₈H₄₆NO₆Si₂ (M⁺ - OCH₃): 548.2864, found 548.2872.

7

The [3+2] cycloaddition was best achieved in CH₂Cl₂ (96%). In benzene, the cycloaddition provided 3 R in 92% yield, and the dr of the adducts was 99:1.

8

We also conducted the Lewis acid (2 equiv)-mediated cycloaddition of 2 with benzonitrile oxide. The results are as follows: 1) BF₃·OEt₂/CH₂Cl₂/-78 °C/6 h (97% recovery of 2), 2) ZnI₂/CH₂Cl₂/-78 °C/6 h (90% recovery of 2), 3) Yb(OTf)₃/CH₂Cl₂/-78 °C/6 h (27% of the adduct, dr = ca 6:1, 47% recovery of 2), 4) MgBr₂/CH₂Cl₂/-78 °C to r.t./6 h (49% of the adduct, dr = ca 7:1, 47% recovery of 2).

9

Compound 4 R: TLC, R_f 0.54 (EtOAc-hexane = 1:6); IR(neat): 3100-2800, 1750, 1600 cm^-1: ¹H NMR (300 MHz, CDCl₃) δ: 0.07, 0.09, 0.10 (total 12 H, 3s), 0.83, 0.92 (each 9 H, each s), 1.10 (3 H, d, J = 6.2 Hz), 1.22 (9 H, s), 3.14 (1 H, dd, J = 11.0, 16.9 Hz), 3.36 (3 H, s), 3.38 (1 H, dd, J = 5.9, 16.9 Hz), 3.65 (1 H, dd, J = 3.3, 9.2 Hz), 3.82 (1 H, dq, J = 6.2, 9.2 Hz), 3.98 (1 H, t, J = 9.2 Hz), 4.62 (1 H, d, J = 3.3 Hz), 4.70 (1 H, t, J = 9.2 Hz), 4.94 (1 H, dd, J = 5.9, 11.0 Hz); ¹³C NMR (75 MHz, CDCl₃) δ: -4.49, -4.43, -3.39, -3.06, 17.30, 17.86, 18.42, 25.86 × 3, 26.14 × 3, 28.05 × 3, 32.80, 37.54, 54.92, 65.19, 71.60, 74.45, 77.81, 77.89, 100.06, 165.83, 169.88; HRMS m/z calcd for C₂₆H₅₀NO₆Si₂ (M⁺ - OCH₃): 528.3177, found 528.3147.

10

(a) Compound 5 R: TLC, R_f 0.19 (EtOAc-hexane = 1:1); IR(neat): 3500(br), 3100-2800 cm^-1; [a]_D ²² -170 (c 1.01, CHCl₃); ¹H NMR (300 MHz, CDCl₃) d 3.28 (1 H, dd, J = 7.9, 16.5 Hz), 3.39 (1 H, dd, J = 10.4, 16.5 Hz), 3.68 (1 H, dd, J = 4.3, 12.2 Hz), 3.87 (1 H, dd, J = 3.1, 12.2 Hz), 4.87 (1 H, dddd, J = 3.1, 4.3, 7.9, 10.4 Hz), 7.37-7.68 (5 H, m); ¹³C NMR (75 MHz, CDCl₃) d: 36.29, 63.63, 81.21, 126.68 × 2, 128.69 × 2, 130.17 × 2, 157.08; HRMS m/z calcd for C₁₀H₁₁NO₂ (M⁺): 177.0790, found 177.0790. (b) Curran and co-workers reported the preparation of 5 R from a 95:5 mixture of the [3+2] cycloaddition of the acryloyl amide of Oppolzer’s chiral sultam with benzonitrile oxide. They obtained the cycloadduct in a dr of 95:5, from which 5 R possessing [a]_D ²⁵ -161 (c 1.0, CHCl₃) was prepared: Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron Lett. 1988, 29, 3555. (c) On the other hand, Akiyama and Ozaki reported the preparation of 5 S, which relied on the [3+2] cycloaddition of the acryloyl ester of optically active cyclitol (l-chiro-inositol) with benzonitrile oxide. By this chiral auxiliary-based methodology, they obtained a 95:5 mixture of the cycloadduct. From the major cycloadduct, 5S possessing [a]_D ²⁵ +172 (c 1.0, CHCl₃) was prepared: Akiyama, T.; Okada, K.; Ozaki, S. Tetrahedron Lett. 1992, 33, 5766.

11

Compound 6 R: TLC, R_f 0.45 (EtOAc); IR(neat): 3480 (br), 3100-2800 cm^-1: [α]_D ²² -120 (c 0.88, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 1.21 (9 H, s), 2.88 (1 H, dd, J = 7.4, 16.7 Hz), 3.02 (1 H, dd, J = 10.4, 16.7 Hz), 3.55 (1 H, dd, J = 4.8, 12.0 Hz), 3.76 (1 H, m), 4.67 (1 H, dddd, J = 3.3, 4.8, 7.4, 10.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ: 3 × 28.03, 33.03, 35.69, 63.76, 80.09, 166.59; HRMS m/z calcd for C₈H₁₅NO₂ (M⁺): 157.1103, found 157.1105. Curran and co-workers reported the preparation of both 6 R and 6 S (each er = 95:5; [α]_D ²⁵
-127 (c 1.0, CHCl₃) for 6 R and [α]_D ²⁵ +124 (c 1.0, CHCl₃) for 6 S by the chiral auxiliary methodology. Using the same methodology, Akiyama and Ozaki obtained enantioenriched 6 S (dr of the cycloadduct = 91:9) possessing [α]_D ²⁰ +121 (c 1.68, CHCl₃). See ref. [10]

12

Retention times of racemic 7: t _R(S) = 17.1 min and t _R (R) = 19.7 min (DAICEL Chiralcel OD-H, 2-propanol-hexane = 1:8).

13

Retention times of racemic 8: t _R (S) = 22.0 min and t _R (R) = 25.2 min (DAICEL Chiralcel OJ-H, 2-propanol-hexane = 1:15).

16

The dr of the cycloadduct 10 was precisely determined by the chiral HPLC analysis after converting the adduct into the isoxazoline derivative 7.